Compound heterozygous mutations in the SSPOP gene lead to epilepsy and developmental disorders.

In polyglutamine disorders, the length of the expanded CAG repeat shows a strong inverse correlation with the age at disease onset, yet up to 50% of the variation in age of onset is determined by other additional factors. Here, we investigated whether variations in the expression of heat shock proteins (HSP) are related to differences in the age of onset in patients with spinocerebellar ataxia (SCA)3. Hereto, we analysed the protein expression levels of HSPA1A (HSP70), HSPA8 (HSC70), DNAJB (HSP40) and HSPB1 (HSP27) in fibroblasts from patients and healthy controls. HSPB1 levels were significantly upregulated in fibroblasts from patients with SCA3, but without relation to age of onset. Exclusively for expression of DNAJB family members, a correlation was found with the age of onset independent of the length of the CAG repeat expansion. This indicates that DNAJB members might be contributors to the variation in age of onset and underlines the possible use of DNAJB proteins as therapeutic targets.

Mapping genes for complex human diseases is a challenging problem due to the fact that many such diseases are due to both genetic and enviromental risk factors and many also exhibit phenotypic heterogeneity, such as variable age of onset. Information on variable age of disease onset is often a good indicator for disease heterogeneity and incorporation of such information together with enviromental risk factors into genetic analysis should lead to more powerful tests for genetic analysis. Due to the problem of censoring, survival analysis methods have proved to be very useful for genetic analysis. In this paper, I review some recent methodological developments on integrating modern survival analysis methods and human genetics in order to rigorously incorporate both age of onset and enviromental covariates data into aggregation analysis, segregation analysis, linkage analysis, association analysis and gene risk characterization. I also briefly discuss the issue of ascertainment correction and survival analysis methods for high-dimensional genomic data. Finally, I outline several areas that need further methodological developments. Survival Analysis Methods in Genetic Epidemiology Running title: Survival Analysis Methods A Chapter in ”Current Topics in Human Genetics: Studies of Complex Diseases” (Eds. Hong-Wen Deng, Hui Shen, Yongjun Liu, Hai Hu) Hongzhe Li Professor of Biostatistics Department of Biostatistics and Epidemiology University of Pennsylvania School of Medicine Philadelphia, PA 19104-6021, USA Email: hli@cceb.upenn.edu 0 Hosted by The Berkeley Electronic Press

Ten Huntington disease (HD) families are analyzed using maximum likelihood methods to study age-of-onset (AO) heterogeneity. Both age of onset and age at examination are used in calculating an individual's likelihood of being affected; familial correlations and family structure are not included in the model. The model allows for differences in current age distributions by considering the distribution of age of onset conditional on age at examination. Families are grouped according to family type (ie, juvenile-onset families and adult-onset families) and then analyzed within each family type as well as between the two types, using both a chi-square test for heterogeneity and F-ratios. The results of the chi-square analyses indicate heterogeneity in AO among the individual families as well as between the two family types. However, the results of the F-ratios show no significant difference between the two family types, indicating that the difference in the chi-square analysis between the two family types is mostly owing to variation among the families. Thus, the results demonstrate that the existing variation in age of onset between these two family types is dwarfed by the magnitude of the variation among the families within each type. This implies that families of sufficient size should be evaluated individually for age-of-onset data for the purpose of either genetic counseling or linkage studies.

Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct

Huntington's disease (HD) is a genetic neurodegenerative disease characterized by cognitive, motor, and psychiatric dysfunction. It is caused by an expansion of the trinucleotide repeat sequence cytosine-adenine-guanine (CAG) in the Huntingtin gene on chromosome 4. Onset typically occurs in the fourth or fifth decade, ranging from childhood to late adulthood. The CAG triplet number is generally inversely proportional to the age of onset (AOO), but the repeat number only accounts for ∼70% of the variability in AOO. Several studies demonstrated the impact of genetic modifiers on age of disease onset. In addition to genetics, we also explored the demographic, anamnestic, and socio-environmental factors that can affect AOO, to help us understand the non-genetic variability of age of onset in HD. We analyzed the retrospective data of the ENROLL-HD global registry study, particularly focusing on the continuum of ages, to include sociodemographic, genetic, and anamnestic psychobehavioral variables in a multivariate regression model aimed at identifying the potential predictors of age of motor onset (n = 5053). We ran the same regression model in the sample of subjects who had the same number of triplets (41 CAG, n = 593) and in the sample whose family history was absent/unknown (n = 630). Patients with delayed onset more frequently have unknown/missing family history, are married or widowed, live in larger urbanized contexts and have a lower educational level. Individuals with earlier onset more frequently develop psychobehavioral symptoms. In the past, the HD gene was considered the epitome of genetic determinism. Our results are consistent with recent evidence that other factors might modulate its impact. These findings allow characterizing the determinants of AOO beyond the CAG expansions and provide valuable information for stratifying patients for future clinical trial designs.

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a progressive neurodegenerative and systemic genetic disease first identified in Portugal, now reported worldwide. During the past few years our knowledge on the phenotypic presentation of this devastating condition has remarkably expanded including a wide variation in age of onset, different neuropathic patterns and patients presenting with isolated or predominant cardiac involvement. Liver transplantation, the first therapeutic approach, although invasive, has been shown to halt the progression of the neuropathy in young onset patients. Fortunately, several disease-modifying treatments are now available or in clinical development including TTR stabilizers and gene therapy. Their efficacy is higher if administered at the earliest disease stage. Thus, management of TTR-FAP patients is a moving field with need for early diagnosis using new diagnostic tools and new therapeutic options.

A European series of 287 cases of "pure" peripheral neuropathy, pooled from 14 neuropediatric centres, has been analysed retrospectively with particular emphasis on the hereditary motor and sensory neuropathies (HMSN) which comprised 241 of the patients. Due to incomplete information in many records it has only been possible to make a crude analysis of the problems of diagnosis and classification. More than half of the HMSN series conform to the diagnosis of HMSN I (charcot-Marie-Tooth-Roussy-Levy disease), A relatively homogeneous group but with large variations in age of onset and severity of disease between individuals in the same family. In five of the 147 cases the onset was at or before birth. An overdiagnosis of HMSN III (Déjérine-Sottas' disease) was considered probable due partly to an unawareness of the high frequency of subclinical carriers among parents in families with HMSN I. Cases with axonal types of polyneuropathy, appearing sporadically or with suspected autosomal dominant (HMSN II) or recessive inheritance, occurred with unexpected frequency in children. This group of 60 pooled European cases was considered worthy of a particularly thorough follow-up and further investigation in order to achieve a better delineation between different subtypes. Cases with an onset before birth or very early in infancy (20 cases) comprised a heterogeneous group with some special subtypes. Surprisingly enough, no less than 5 of the 20 cases represented HMSN I. Cerebrospinal fluid protein levels were not found to be useful for differentiating various types of HMSN. Elevated levels were revealed in about half of the examined cases of HMSN I and in 75% of cases of HMSN III, the levels of increase showing a marked overlap. In nearly all of the axonal cases investigated the CSF protein was normal.

HP, an autosomal dominant disorder with incomplete penetrance has been reported in 13 families and is characterized by chronic relapsing pancreatitis leading to pancreatic insufficiency, pancreatic calcifications, and at times diabetes. In 3 of the original families lysine-cystine amino-aciduria was present in some members regardless of pancreatic involvement.Our West Va. kindred (total 55 members) had 8 definite and 12 suspected cases of pancreatitis, mean age of onset 5 yrs.: 7 of 8 definite cases had pancreatic lithiasis, in 3 instances before 13 yrs. of age. Our Tenn. kindred (total 110 members) had 9 definite and 12 suspect cases, mean age of onset 14 years, with 6 of 9 definit cases presenting calcifications. There was striking variation in age of onset from 18 mos. to 35 yrs. Steatorrhea and pancreatic deficiency tended to be a late complication but they were found as early as 20 yrs. of age. There was no good clue as to what brought on acute attacks.In both kindred fecal fat, pancreatic enzymes, and serum amylase and lipase were assessed. Serum lipids and parathyroid function by calcium infusion were normal. All urinary amino acids were determined in 7 patients and 9 relatives and were normal in all instances.HP is a generally unrecognized cause of pancreatitis in childhood and important in the differential diagnosis of recurrent abdominal pain and pancreatic lithiasis (e.g., from cystic fibrosis). It is speculated that two different genetic types of HP exist with and without amino-aciduria.

The recent study by van der Weijden et al. proposed defining hidradenitis suppurativa (HS) in the elderly (> 60 years of age) as ‘HS tarda’. We verify and extend the findings by van der Weijden et al. by demonstrating that variation in HS severity is explained to an increasing extent by sex with increasing age, but is independent of overall disease duration, and that HS in the elderly shows significant variation in age of onset and body area involvement. This supports the idea that HS activity varies between different age groups, but the relationship remains more complex than a binary definition.

Heritability of Hearing Loss

Limb-girdle muscular dystrophy R8 (LGMD R8) is a hereditary muscle disease caused by biallelic defects in E3 ubiquitinated ligase gene (TRIM32). LGMD R8 is featured by high genetic heterogeneity and phenotypic diversity, most pathogenic variants are missense variants located in the NHL domain, but the genotype-phenotype correlation remains unclear. We hypothesized that various missense variants in NHL domain might have different degrees of impact on the structure and function of the protein, thus resulting in disease variability. Firstly, by analyzing present patients’ clinical data, we screen out 4 variants: R394H, D487N, V591M and P619S. Patients homozygous for the aforementioned variants exhibited significant phenotypic variability, including variations in age of onset and age of any walking aid (AWA). Then, bioinformatics analysis, cellular functional experiment and biophysical assay were used to measure the effect of above variants in TRIM32 protein oligomerization and ubiquitination to target substrates. And they revealed distinct differences in the intrinsic E3 ligase activity among various mutant TRIM32 proteins, which corresponded to differences in their oligomerization status. In conclusion, our results showed a correlation between clinical severity, protein function and oligomerization state in patients homozygous for missense variants in NHL domain. It is the first time to reveal a connection between TRIM32 variant with LGMD R8 phenotype and this finding provided valuable reference in predicting disease severity and more precise guidance to affected family on genetic counseling.

Maroteaux-Lamy disease (MPS Type VI) is an autosomal recessive lysosomal storage disorder. Skeletal abnormalities are vast. Early recognition may facilitate timely diagnosis and intervention, leading to improved patient outcomes. The most challenging is when patients manifest a constellation of craniocervical and articular deformities with variable age of onset. We collected 15 patients with MPS VI (aged from 6 years-58 years). From within our practice in Pediatric Orthopedics, we present patients with MPS type VI who were found to manifest a diverse and confusing clinical presentation of hip deformities and cervical cord compression. Stem cell transplants were proposed as treatment tool and enzyme replacement therapy has been instituted in some patients. The spectrum of the clinical involvement in our group of patients was supported firstly via the clinical phenotype followed by assessment of the biochemical defect, which has been detected through the deficiency of N-acetylgalactosamine-4-sulfatase (arylsulphatase B) leading to increased excretion of dermatan sulphate. Secondly, through the molecular genetic results, which showed homozygous or compound heterozygous mutation in the ARSB gene on chromosome 5q14. Hip replacements and decompression operations have been performed to restore function and to alleviate pain in the former and life saving procedure in the latter. The efforts in searching for the etiological diagnosis in patients with skeletal dysplasia/MPSs has not been rewarding as many had anticipated. This emerged from several facts such as improper clinical documentation, missing diagnostic pointers in radiographic interpretations, limited knowledge in skeletal dysplasia and its variants, and the reliance on underpowered studies. Physicians and radiologists are required to appreciate and assess the diverse phenotypic and the radiographic variability of MPS VI. The importance of considering MPS in the differential diagnosis of other forms skeletal dysplasia is mandatory. Finally, we stress that the value of early diagnosis is to overcome dreadful complications.

Caregiving for older relatives is central for many people's lives in aging societies. The timing of caregiving onset significantly influences caregivers' health, social, and employment trajectories. However, the age at which family caregiving begins and its potential social and intersectional stratification have not been sufficiently explored. Using data from the Survey of Health, Ageing and Retirement in Europe (SHARE), we analysed individuals becoming daily caregivers between waves 1 and 9 (ages 50–95). We applied Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy (MAIHDA) to determine intersectional inequalities in the age of caregiving onset, separately for intragenerational (partner, siblings) and intergenerational (parents, in-laws) caregiving. We created 48 intersectional strata with combinations of sex/gender, migration background, education, and occupation. Intragenerational care onset was at 70.18 years on average (N = 10,146), with 11 years of difference between strata. Intersectional strata explained substantial variation in onset age (VPC = 7.14%), and 10% of these differences were due to intersectional interaction effects. Intergenerational care (N = 3,966) began earlier at 59.56 years on average, with a difference of over 4 years between strata. Most between-strata variation was additive. For both intra- and intergenerational care, combinations of women with low-skill occupations and high education were associated with earlier caregiving onset. We found large differences in the age of caregiving onset between intersectional strata in both intra- and intergenerational care. Mapping social heterogeneity and the intersectional nature of caregiving onset within the life-course is critical to further understand the prerequisites, meaning, and consequences for family caregivers.

Age- and sex-specific prevalence of diabetes associated with diseases of the exocrine pancreas: A population-based study

<div>Abstract<p><b>Background:</b> We propose a 2-step model-based approach, with correction for ascertainment, to linkage analysis of a binary trait with variable age of onset and apply it to a set of multiplex pedigrees segregating for adult glioma.</p><p><b>Methods:</b> First, we fit segregation models by formulating the likelihood for a person to have a bivariate phenotype, affection status and age of onset, along with other covariates, and from these we estimate population trait allele frequencies and penetrance parameters as a function of age (<i>N</i> = 281 multiplex glioma pedigrees). Second, the best fitting models are used as trait models in multipoint linkage analysis (<i>N</i> = 74 informative multiplex glioma pedigrees). To correct for ascertainment, a prevalence constraint is used in the likelihood of the segregation models for all 281 pedigrees. Then the trait allele frequencies are reestimated for the pedigree founders of the subset of 74 pedigrees chosen for linkage analysis.</p><p><b>Results:</b> Using the best-fitting segregation models in model-based multipoint linkage analysis, we identified 2 separate peaks on chromosome 17; the first agreed with a region identified by Shete and colleagues who used model-free affected-only linkage analysis, but with a narrowed peak: and the second agreed with a second region they found but had a larger maximum log of the odds (LOD).</p><p><b>Conclusions:</b> Our approach was able to narrow the linkage peak previously published for glioma.</p><p><b>Impact:</b> We provide a practical solution to model-based linkage analysis for disease affection status with variable age of onset for the kinds of pedigree data often collected for linkage analysis. <i>Cancer Epidemiol Biomarkers Prev; 21(12); 2242–51. ©2012 AACR</i>.</p></div>